Altering Cardiac Cell Fate for Heart Repair

改变心肌细胞命运以修复心脏

• 批准号: 10328550
• 负责人: Li Qian
• 金额: $ 92.81万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-13 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10328550
• 关键词: Acute myocardial infarction; Cardiac; Cardiac Myocytes; Cardiovascular Physiologic Processes; Cells; Cicatrix; Development; Disease; Doctor of Philosophy; Fibroblasts; Funding; GATA4 gene; Grant; Heart; Heart Diseases; Heart Injuries; Heart failure; Human; Impairment; Knowledge; Laboratories; Mechanics; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardium; National Heart, Lung, and Blood Institute; Natural regeneration; Pathologic Processes; Patients; Post-Transcriptional Regulation; Postdoctoral Fellow; Pump; System; Time; Tissues; Training; Transcriptional Regulation; cardiac repair; clinical application; epigenetic regulation; functional improvement; improved; in vivo; in vivo evaluation; insight; mathematical model; mortality; multiple omics; novel; novel therapeutics; public health relevance; regeneration potential; response to injury; stem cell biology; transcription factor

Abstract Direct cardiac reprogramming holds great promise as a novel therapy for heart failure, a common and morbid disease that is usually caused by irreversible loss of massive functional cardiomyocytes. By leveraging the knowledge in developmental and stem cell biology gained during my PhD and postdoc training, in 2012 I demonstrated that in a murine acute myocardial infarction model, delivery of three transcription factors, Gata4, Mef2c and Tbx5 (GMT) converted cardiac fibroblasts (CFs) into functional induced cardiomyocytes (iCMs) that integrated electrically and mechanically with surrounding myocardium, resulting in functional improvement and scar size reduction. These findings suggest that iCM reprogramming is an effective means of regenerating heart tissue in vivo for human patients with heart disease. However, because relatively little was known about the factors that allow CFs to be reprogrammed, the applicability of cardiac reprogramming was limited to the context in which it had been attempted at that time. Since my independence, my own laboratory has established robust murine and human iCM reprogramming systems. By using these systems, we obtained novel insights into the transcriptional, post-transcriptional and epigenetic regulation of both murine iCM (supported by R01HL128331 as ESI) and human iCM reprogramming (supported by R01HL144551), and concomitantly improved the quality and yield of iCMs. This R35 EIA application is an extension to these two currently funded NHLBI R01 grants to further unravel the molecular mechanisms underlying iCM conversion, to test in vivo iCM reprogramming in non- acutely injured hearts and to exploit the latest single cell multi-omics and mathematical modeling for optimized and individualized reprogramming. Successful completion of this proposal will help to move direct cardiac reprogramming closer to its clinical application, provide new insights into molecular mechanisms underlying cardiac cell fate determination, and open new opportunities for the field to leverage the models and platforms we will develop here to study other cardiovascular physiological and pathological processes.

抽象的 直接心脏重编程作为治疗心力衰竭（一种常见且病态的疾病）的新型疗法具有广阔的前景 通常是由大量功能性心肌细胞不可逆损失引起的疾病。通过利用 2012 年，我在博士和博士后培训期间获得了发育和干细胞生物学方面的知识 证明在小鼠急性心肌梗死模型中，三种转录因子 Gata4、 Mef2c 和 Tbx5 (GMT) 将心脏成纤维细胞 (CF) 转化为功能性诱导心肌细胞 (iCM)， 与周围心肌进行电气和机械整合，从而改善功能并 疤痕尺寸缩小。这些发现表明 iCM 重编程是心脏再生的有效手段 人类心脏病患者的体内组织。然而，由于人们对它知之甚少 允许 CF 重新编程的因素，心脏重新编程的适用性仅限于上下文 当时就曾尝试过。自从我独立以来，我自己的实验室已经建立了强大的 小鼠和人类 iCM 重编程系统。通过使用这些系统，我们获得了新的见解 小鼠 iCM 的转录、转录后和表观遗传调控（由 R01HL128331 支持） 如ESI）和人类iCM重编程（由R01HL144551支持），并同时提高质量 和 iCM 的产量。此 R35 EIA 申请是这两项目前资助的 NHLBI R01 赠款的延伸 进一步揭示 iCM 转化的分子机制，以测试非体内 iCM 重编程 严重受伤的心脏，并利用最新的单细胞多组学和数学模型进行优化 以及个性化的重新编程。该提案的成功完成将有助于直接推动心脏 重编程更接近其临床应用，为潜在的分子机制提供新的见解 心肌细胞命运决定，并为该领域利用模型和平台带来新的机会 我们将在这里发展研究其他心血管生理和病理过程。